Derivatives of 6-amino penicillanic acid

ABSTRACT

Derivatives of polyfunctional compounds such as dicarboxylic acids, diisocyanates or diisothiocyanates wherein one functional group is reacted with 6-APA and one functional group is reacted with 7-ACA or 7-ADCA possess antibacterial activity.

United States Patent 11 1 [1 11 3,882,100

Perrella et al. May 6, 1975 DERIVATIVES 0F 6-AMINO PENICILLANIC 3,632,578 1 1972 Clauvette 260/2391 ACID I FOREIGN PATENTS OR APPLICATIONS [75] lnwtmors. 6322? 695,83] 10/1964 Canada 26U/239.l

Princeton, both of NJ.

i Primary ExaminerNicholas S. Rizzo Abslgnfie' t rgf Sons Assistant ExaminerMary C. Vaughn rmce Attorney, Agent, or FirmLawrence S, Levinson; {22] Filed: Sept. 22, 1972 Merle J. Smith; Stephen B. Davis [2i] Appl, No.: 291,443

[ ABSTRACT [52] U.S. Cl. .i 260/239.l; 424/246; 424/27] [5]] C07d g 99/24 Dcnvatn cs of polyft nctlonal compounds such as d!- [58] Field of Search 260/2391 243 C carboxyhc acids, dusocyanates or diisothiocyanates wherein one functional group is reacted with 6-APA [56] References Cited and one functional group is reacted with 7-ACA or 7- ADCA possess antibacterial activity.

11 Claims, N0 Drawings DERIVATIVES OF 6-AMINO PENICILLANIC ACID The present invention relates to antibacterial agents. and more particularly. to antibacterial agents containing one fi-aminopenicillanic acid (b-APA) moiety and either one 7aminocephalosporanie acid (7ACA) moiety or 7-aminodcsacetoxycephalosporanic acid (7- ADCA) moiety.

It is an object ofthe present invention to provide new antibacterial agents. Another object is to provide antibacterial agents of improved efficacy. A further object is to provide antibacterial agents which contain at least one o-APA moiety and either one 7-ACA or one 7- ADCA moiety. Still another object is to provide antibacterial agents from dior higher polyfunctional compounds. These and other objects of the present invention will be apparent as the description proceeds.

SUMMARY OF THE INVENTION The antibacterial agents of the present invention comprise derivatives of di or higher polyfunctional compounds such as dior higher polycarboxylic acids or di or higher polyisocyanates or isothiocyanates wherein one functional group is reacted with 6- aminopenicillanic acid (6APA) and one functional group is reacted with either 7-aminoccphalosporanic acid (7-ACA] or 7-aminodesacetoxycephalosporanic acid (7-ADCA).

DETAILED DESCRIPTION The dior higher polyfunctional starting compounds of the present invention comprise dior higher polycarboxylic acids or dior higher polyisoeyanates or dior higher polyisothiocyanates. At least one functional group of the starting compound is reacted with o-APA and at least one functional group is reacted with 7-ACA or 7-ADCA. By way of illustration. one car boxy] group of a dicarhoxylic acid may be reacted with the amino group of 6-APA and the other carboxyl group reacted with the amino group of 7-ACA or 7- ADCA. In the case of a diisocyanate or isothiocyanate. one isocyanate group or isothioeyanate group may be reacted with the amino group of o-APA and the other isocyanate or isothioeyanate group may be reacted with the amino group of 7-ACA or 7-ADCA.

Various types of poly functional compounds may be used in the present invention. The polyfunctional com pound may be aliphatic. alicyclic. aromatic or heterocyclic. By way of illustration. some examples for each group follow.

I. Polycarboxylic Acids homophthalic. o-phenyleneacctiuiipropionic acid.

etc.

4. Heterocyclic acids pyridine-3.4-dicarboxylic acid. quinolinic acid. y-pyran-lb-dicarhtisylic acid. chelidonic acid. pyridine-I.BA-Iricarboxylic acid. thiophenci.5-dicarboxylic acid. etc.

It will be understood by those skilled in the art that the polycarboxylic acid may be reacted as such or in (ill the form ofits acyl anhydride. activated ester. acyl halide. i.e.. the acyl chloride or acyl bromide. etc.

ll. Polyisocyanates and Polyisothioeyanates l. Aliphatic isocyanates ethylene diisocyanatc. propylenel .2-diisocyantate. butylcnc l .3-

diisocyanate. tetramethylene diisocyanate. pentameth= ylenc diisocyanate. hexamethylenc diisocyanate. butane-l.2.4-triisocyainate. etc.. and the corresponding isothiocyanates;

2. Aromatic isoeyanates p-phcnylcnc diisocya nate. 2.4-tolylenediisocyanate. 2.4-chlorophcnylene diisocyanate, 2.6tolylenediisocyanate. diphcnyl4.4'- diisocyanatc. p-isocyanatobenzyl isocyanate. diphenylmethane-4.4 '-diisocyanate. 3.3 'bitolylcne-4.4 diisocyanate. 3.3'-dimethyldiphenylrnethane-4A'- diisocyanate. l.2.4-benzene triisocyanate. l.2.5- benzene triisocyanate. etc.. and the corresponding isothiocyanates;

3. Alieyclic isocyanatesl .2-diisocyanocyclohexanc. l.3-diisoeyanocyclohcxanc. l .4- diisoeyanocyclohcxane. cyclopcntyll Jaliisocyanate. etc. and the corresponding isothiocyanates;

4. Heterocyclic isoeyanates pyridine-2f diisocyanate. (uran-lfi-diisocyanate. thiophcnc'l-ldiisocyanate. thiophene-lS-diisoeyanate. pyrimidine- 4.6-diisocyanate. pyrimidine-4.5.o-triisocyanate. etc. and the corresponding isothiocyanates.

The compounds of the present invention include the free acids as well as physiologically acceptable metal salts. esters. or salts ot physiologically acceptable or ganic bases. Examples of suitable metal salts include the alkali metal and alkaline earth metal salts. cg. the Na. K. Mg and Ca. The ammonium ion may be included among the alkali metals. Examples oi suitable esters include radicals derived from alcohols of up to 7 carbon atoms. e.g.. methyl. propyl. t-butyl. trichloroethyl, pivaloyloxymethyl. benzyl. p-nitrophenyl. trimethylsilyl. trimethyl stannyl. methoxymethyl. and the like. Examples of suitable bases include substituted ammonium salts. cg. salts of nontoxic amines such as trialkylamines. including tricthylamine. procaine. diben zylamine. N-benzyl-[i-phenethylaminc. N.N' dibcn/ylethylenediamine. N-(lower)alkylpiperidine. e.g.. N-ethylpiperidine and other amines which have been used to form salts with bemylpenicillin and the like. The foregoing metal salts or organic bases and esters are prepared according to known techniques.

The compounds of this invention form salts which are also part of the invention. Basic salts form with the carboxy] group of either the o-APA moiety or the 7-ACA or 7-ADCA moiety. It is frequently convenient to iso late and purify the product by forming a soluble or insoluble salt. as desired. then regenerating the free compound. by neutralization for example.

The compounds of this invention have a broad spec trum of antibacterial activity against both gram positive and gram negative organisms such as .Sruphylucoer-ax uurem. Salmonella .s't'lirimiiiwllt'ri. PMHdrHHUIIUS urrugirmsu. Proteus vii/gun's. list'lrerirliiu cult and Streptococ- ('us pyogcnm. They may be used as antibacterial agents in a prophylactic manner. cg. in cleaning or disinfect ing compositions. or otherwise to combat infections due to organisms such as those named above. and in general maybe utilized in a manner similar to penicillin G and other penicillins and cephalosporins. For example. a compound of the invention or a physiologically acceptable salt thereof may be used in various animal species in an amount of about l).l to lllll mg/kg daily. orally or parenterally. in single or two to four divided doses to treat infections of bacterial origin. lip to about 600 mg of a compound of the invention or a salt thereof may be incorporated in an oral dosage form such as tablets. capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conven tional pharmaceutical practice. ln cleaning or disinfecting compositions. e.g.. in barns of dairy equipment. a concentration of about 0.0] to E9? by weight of such compounds admixed with. suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying may be used.

The componds of the present invention may be readily prepared by reacting 7-ACA or 7ADCA. the carboxyl group of which is protected with trimethylsilyl chloride at about room temperature. The foregoing rcactants are present in about equimolar quantities. The reaction takes place in an inert solvent such as. for example. chloroform. benzene. toluene. ethylene chloride. methylene chloride, dioxane. nitromethane. acetonitrile dimethylformamide or dicthyl ether. or mixtures of two or more of the foregoing solvents. The car boxyl group of the 7-ACA or "LADCA moiety may be protected by any convenient ester group which will not interfere with reaction between the amino group of either the 7-ACA or 7-ADCA moiety and either the isocyanate or isothiocyanate compound. The reaction takes place at temperatures in the range of from about 30C to about 20C.

FORMATION OF POLYCARBOXYLIC ACID PRODUCT After the reaction between the 7-ACA or 7-ADCA and trimethylsilyl chloride has gone to completion. after about one hour. about an equimoiar quantity of polycarboxylic acid as the anhydridc. mixed anhydride. or other activated form and triethylamine are added with agitation for about one hour. After cooling to from about -lt) to about 10C, preferably to about 0C. about one equimolar quantity of ethyl chloroformate is added. After a short period of time. from about It) to about minutes. about one equimolar amount of (PAPA and about I cquimolar amounts of triethylam inc in chloroform are added. Cooling is discontinued and the reaction allowed to proceed for about one hour. whereby the desired polycarboxylic acid product is obtained. Alternatively. an acid chloride may be used instead of the anhydride. in which case there is no need to add ethyl chloroformate at an intermediate stage of the reaction.

FORMATION OF POLYISO (OR lSOTHlO) CYANA'IE PRODUCT After the reaction between the 7-ACA or TADCA and trimethylsilyl chloride has gone to completion. after about one hour. about an cquimolar quantity of polyisocyanate or polyisothiocyanate are added with agitation for about l hour. After cooling to from about lU to about lUC. preferably to about 0C. about one equimolar amount of o-APA and about 2 cquimolar amounts of triethylamine in chloroform are added. Cooling is discontinued and the reaction allowed to proceed for about hour. whereby the desired polyisoeyanate or polyisothiocyanate product is obtained.

While examples of specific polycarboxylic acids and polyisocyanatcs or polyisothiocyanates have been given previously. it is to be understood that any polycarboxylic acid. polyisoeyanatc or polyisothiocyanate may be employed according to the present invention provided no substituents are present which would interfere with the reaction with the antibacterial moiety. With the foregoing understanding. the following paragraphs describe preferred compounds.

The aliphatic polycarboxylie acids. examples of which have been given previously. comprise polyalkanoic or polyalkenoie acids of from two to about l2 carbon atoms (including those in the carboxyl groups). The acid may be substituted. e.g.. by a halogen.

The alicyclic polycarboxylic acids. examples of which have been given previously. comprise cycloalkyl or cycloalkcnyl compounds of five or six carbon atoms in the ring. and a total of from seven to about 10 carbon atoms (including those in the carboxyl groups). or a bicyclic ring system having a total of about nine carbon atoms (including those in the carboxyl groups).

The aromatic polycarboxylic acids. examples of which have been given previously. comprise benzene polycarboxylic acids having from eight to l() carbon atoms. or homologs thereof having from nine to 12 carbon atoms (including those in the carboxyl groups).

The heterocyclic polycarboxylic acids. examples of which have been given previously. comprise fiveor six-membered rings containing :1 single hetero-atom which may be N. O or S. and having a total of four to eight carbon atoms (including those in the carboxyl groups).

The aliphatic polyisocyanates or polyisothiocyanates. examples of which have been given previously. c0mprise polyisocyanates or polyisothiocyanates of from two to about 10 carbon atoms (including those in the isocyanate or isothiocyanate groups).

The aromatic polyisocyanates or polyisothiocyanatcs. examples of which have been given previously. comprise benzene 0r benzyl polyisocyanates or polyisothiocyanates of from eight to about 10 carbon atoms (including those in the isocyanate or isothiocyanate groups) or a benzene isocyanate or isothiocyanate joined directly or through a methylene group to a sec ond benzene isocyanate or isothiocyanate. respectively. in which case the compound has from l4 to about 17 carbon atoms (including those in the isocyanate or isothiocyanate groups). The benzene rings may be substituted. e.g.. by a halogen atom. or by methyl groups as long as the upper limits of carbon atoms are not exceeded.

The alicyclic polyisocyanates or polyisothiocyanates. examples of which have been given previously. corn prise cycloalkyl compounds of five or six carbon atoms in the ring which carbons may be substituted by a methyl group or by a halogen. and which compounds have a total of from seven to about lU carbon atoms (including those in the isocyanate or isothiocyanatc groups).

The hcterocyclic isocyanates or isothiocyanates. examples of which have been given previously. comprise fiveor six-mcmbered rings containing a single heteroatom which may be N. (J. or S. or two nitrogen heteroatoms. and which have a total of from six to about eight carbon atoms (including those in the isoeyanate or isothiocyanate groups The following examples are illustrative of the invention. All temperatures are in degrees Celsius unless otherwise stated.

EXAMPLE 1 Succinoyl N-( 7-Aminodesacctoxycephalosporanic Acid) l\l'-(o-Aminopenicillanic Acid) A solution of one mmole of 7-ADCA and 2 mmoles of triethylamine in 30 ml of pure chloroform at ambient temperature is treated with l mmole of pure trimethylsilvl chloride. After stirring for l hour. one mmole of succinic anhydride is added with l mmole of additional triethylamine The mixture is stirred for about I hour. After chilling to C. 1 mmole of ethyl chloroformate is then added. After minutes a solution of l mmole ofo-APA and 2 mmoles of triethylamine in chloroform are added. The coolant is then removed and the reaction allowed to proceed for 1 hour. The reaction is then diluted with an equal volume of chloroform and extracted with several portions of cold 0.] N aqueous hydrochloric acid. then washed with water. The organic solution is extracted with several volumes of pH 7.5 phosphate buffer. The aqueous extract is then acidified to about pH 3.5 and extracted with several volumes of ethyl acetate. The ethyl acetate extract is washed with water, then dried (Na SO and evaporated at reduced pressure to deposit the title compound.

EXAMPLES 2-5 Following the procedure of Example 1 but substituting for succinic anhydride 1 mole of the compound listed in Column l, the product obtained is indicated in Column ll.

Ex. I ll 'letrahydrophthalic anhydride Tetrahydrophthaloyl N-t 7-aminodcsacctox}ccphalosporanic acid)-N'-t fi-aminopcnicillanic acid) Hcxah)dfophtht|lo)'l N4 7- aminodcsaceto txccphalo' sporanic acid)-N-1o-aminw penicillanic acid) Ouinolinoyl N4 7-aminudcsacetiixycephalosporanic acid )-N (1an1inopcnicillanic acid) Cinchomcroyl N-t lamint dcsaceto ccphalosporanic acid)-N'-(h-aminopcnicillanic acid) 3 Hexahtdrophthalic anh dridc 4 Quinolinic anhydndc 5 Cinchomeronic anh dritlc EXAMPLE 6 (jlutaroyl N-(7-Aminocephalosporanic Acid)N'-( o Aminopcnicillanic Acid) Following the procedure of Example 1 but substitut' ing 1 mmole of glutaric anhydride for succinic anhydridc. and substituting l mmole of 7-ACA for 7- ADCA. the title compound is obtained.

ethylamine. The mixture is stirred for about 1 hour. After chilling to 0C. 1 mmole of ethyl chloroformate is then added. After 15 minutes a solution of l mmole of 7-ACA and 2 mmoles of triethylamine in chloroform is added. The coolant is then removed and the reaction allowed to proceed for l hour. The reaction is then diluted with an equal volume of chloroform and extracted with several portions of cold 0. lN aqueous hy drochloric acid. then washed with water. The organic solution is extracted with several volumes of pH 7.5 phosphate buffer. The aqueous extract is then acidified to about pH 3.5 and extracted with several volumes of ethyl acetate. The ethyl acetate extract is washed with water, then dried (M1 50 and evaporated at reduced pressure to deposit the product.

EXAMPLE 8 Adipoyl N-( 7-Aminodesacetoxycephalosporanic Acid)-l\l'-(o-Aminopenicillanic Acid) Following the procedure of Example 1 but eliminating the addition ofethyl chloroform-ate and substituting l mmole of adipoyl chloride in place ofsuccinic anhydride. the title compound is obtained.

EXAMPLE 9 Sebacoyl N-( 7-Aminocephalosporanic Acid)-N'-(o-Aminopenicillanie Acid) Following the procedure of Example 7 out eliminating the addition ofethyl chloroformate and substituting l mmole of sebacoyl chloride in place ofsuccinic anh vdride. the title compound is obtained.

EXAMPLE l0 Phthaloyl-N-( 7-Aminocephalosporanic Acid )-N'-(o-Aminopenicillanic Acid) Following the procedure of Example 7 but substituting 1 mmole of phthalic anhydride in place of succinic anhydride. the title compound is obtained.

EXAMPLE I l Phthaloyl-N-( 7-Aminodesacetoxycephalosporanic Acid)-N'-(-Aminopenicillanic Acid) Following the procedure of Example l but substituting 1 mmole of phthalic anhyride in place of succinic anhydride. the title compound is obtained.

EXAMPLE l2 Hexahydrophthaloyl-N-( 7-Aminocephalosporanic Acid J-N 6-Aminopenicillanic Acid) Following the procedure of Example 7 but substituting 1 mmole of hexahydrophthalic anhydride in place of succinic anhydride. the title compound is obtained.

EXAMPLE l3 Tetrahydrophthaloyl-N-( 7-Aminocephalosporanic Acid)-N'-(o-Aminopenicillanic Acid) Following the procedure of Example 7 but substituting 1 mmole of tetrahvdrophthalic anhydride in place of succinic anhydride, the title compound is obtained.

EXAMPLE l4 Endomethylenetetrahydrophthaloyl-N( 7-Aminocephalosporanic Acid)N'-( 6-Aminopenicillanic Acid) Following the procedure of Example 7 but substituting 1 mmole of cndomethylcnetetrahydrophthalic an- EXAMPLE 1) hydride in place ot succinic anhydride the title com- Pound is obtiined IAyhcnyicncdmmmeflNl 7- (arbonylaminodesacettmyccphalosporanic Acid) N'-(o-Carhonylaminopenicillanic Acid) [:XAMPLE l 5 v i i Following the procedure ot Example I but eliminating the ethyl chlorotorniate and substituting l mmole ol' l 4-phenylenediisocyanate t'or succinic anhydride.

Following the procedure of Example 7 but suhstitut the title compound is obtained. in i I mmole of cam ihoric anhvdride in wlac of suc 1 l a .5 1 l EXAMPLb cinic anhydnde. the title compound is obtained.

l A-Cyclohexyldiamine-N-( 7- EXAM E [(1 Carbonylaminodesacetoxycephalosporanic Acid l-N l (i'Carbonylaminopenicillanic Acid) CamphoroyLN-t 7-Aminocephalosporanic Acidl-N-((Aminopenicillanic Acid) CamphoroyLNi7-Aminodesacetoxycephalosporanic v 4 i N' (h Amin0pniCi||aniC Add) Following the procedure ot [:xample l but eliminating the ethyl chloroformate and substituting l mmole of l,4-cyclohexyldiisocyanate for succinic anhydride the title compound is obtained.

Following the procedure of Example I but substituting 1 mmole of camphoric anhydride in place of succinic anhydride the title compound is obtained.

20 EXAMPLE 2] EXAMPLE I Z (1-Pyridyldiamine-N-(7- Quinolino vlN-( 7-Aminocephalosporanic Carbonylaminodesacetoxyccphalosporanic Acid)-l\l'-(o-Aminopenicillanic Acid] Acid)-N'-(o-Carbonylaminopenicillanic Acid) Following the procedure of Example 7 but suhstitut- Following the procedure of Example I but climinab ing l mmole of quinolinic anhydride in place of suc i the ethyl ehlorotormate and substituting I mmole cinic anhydride, the title compound is obtained. of pyridine-ltvdiisoeyanate for succinic anhydride, the

title compound is obtained.

EXAMPLP 18 3t] EXAMPLES 2243 EthylenediamineN-( 7- Carbonylaminodesacetoxycephulosporanic Acid )-l\l'( fi-Carbonylaniinopenicillanic Acid) Following the procedure of Example 1 but eliminating the ethyl chlorol'orrnate and substituting for succinic anhydride 1 mmole of the compound in Column Following the procedure of Example I but eliminat- I, there is obtained a compound of the following foring the ethyl chloroformate and substituting l mmole mula s 1 i u s V C I l l 3 ti t k li t l- & wCh ---CE1 C l l l l 1 cu l. r en u L CH J ll (1' c i I 1 CU ll of ethylene diisocyanatc for succinic anhydride. the wherein R is the radical indicated in Column H and Y title compound is obtained. is as indicated in Column 111.

' 12L: ii. 1.3 iii 22 liTlVtl/liflfl l,x il i.,ii liioy n- H Cii CiI CH 8 L4 Yummy} in -l r'Tlllfllllj i'lilrlt j CH ZI fiH O Ttrjui l' i my i' zl i3 -CEI Cii Ci-I Ctl 5 25 Pentarnethylene di ic anate C (,H (crt 3 H 0 26 Hexamethylene diisothioc' anate CH2 (CH2 4CH2 S EXAMPLE 44 Ethylenediamine-N(7-Cz1rbonyluminoccphalosporunic Acid )-N'(o-Curbonyltiminopcnicillanie Acitl) Following the procedure of Example 7 but eliminzlt ing the ethyl chlorotormute and substituting l mmole ofethylenediisocyamutc for succinic unhytlridc the title compound is obtained.

EXAMPLE 45 l.4Phen lcnedinmineNl 7-Curbonyluminoccphulos' porunic Acid )-N '4 oCurbonl \'nminopcnicillunic Acid) Following the procedure of Example 7 but eliminut ing the cthylchloroformnte and substituting l mmole of l.4phenylenediisocyunnte for succinic anhydride the title compound is obtained EXAMPLE 46 l -l-Cyclohexyldiumine-N-( 7(arbonyluminocephalosof I:Lcychihexyldiisocyanate for succinic unhydride, the title compound is obtained EXAMPLE 47 2,6-Pyridyldiumine-N4 7-Carbonylaminocephalosporunic Acid)-N'-(fi-Carbonylaminopenicillanic Acid) Following the procedure of Example 7 but eliminating the ethyl chloroformate and substituting l mmole of pyridinc-2,6-diis0cyunate for succinic anhydride, the title compound is obtained.

EXAMPLES 48-69 Following the procedure of Example 7 but climinuv ing the ethyl chloroformute and substituting for succinic anhydride 1 mmole of the compound in Column I there is obtained a compound of the following forporunic Acid)-N-(fi-Czirhonylnminopenicillunic Acid) 2U mula S H Y H H Y H S l llll HUC LH -CHN(,NRNCNCHCH C 7 l l l i l cq v 3 T M I HECOL OCHZ k,i\\ I C\\\\U OC N Cii COZH Following the procedure of Example 7 but eliminatwherein R is the radical indicated in Column ll and Y ing the ethyl chloroformate and substituting l mmole is its indicated in Column lll.

Example ,g l I III 48 Propylene-l,2cli.isothio cyanette L t cri cl S 49 B yl n 3diis3cyanate CEl CH (i;{-[ 0 CH3 5O Icztrarnetnylene diiso l/Unfit? CH CEi CEi C S 51 Pentnmecnyl n diisocya'iate CH (CH CH O 52 Haxamethylene diisothiocyztnute CH (CH CH S 53 -Phenylene c'liisothio CH cyanate 3 S4 2,4Tolylene cliiso- C cyanate Q 0 55 2,4-Chlorophenylene dicl isocyanate Q 56 2,6-Tolylene diisothio CH3 cyanate s wherein R is an aliphatic hydrocarbon group of from two to carbon atoms. u monocyclic nlicyclic group of fixc or six curhon utoms in the ring; 11 bicyclic alicyclic group of eight to 10 carbon atoms; henzyl. chloro 3 A cumpmmd according to Claim 1 wherein X is phenyl. phenyl or tolyl the phenyl or tolyl groups op- 5 tionull mat he joined to ll second phenyl or tolyl group H O direetl or through a methylene group; or n tire or six i i memhered monohetcrocyclic group wherein the het' eroutom is N. O or S. or a fiveor siicmemhered diheteroc wlic group wherein each hetcroatom is N: X is 4. A compound according to chum 1 wherein X is 5. A compound according to claim 2 wherein O is CH OCOCH 6. A compound according to claim 2 wherein Q is i CH;;.

7. A compound according to claim 3 wherein Q is CH OCOCH 8. A compound according to claim 3 wherein O is n is l) or l. but may he zero only when X is Q is *(H or CHJJCOCH and Z is hydrogen, a

physiologically acceptable metal. NH 11 physiolog- CHI ieull acceptable orgunic amine selected from triethyl- Compound according to Claim 4 wherein Q zunine. rocaine. dihenzylumine. N-henzyl B- (H,,()(()CHT phenethflumine. N Ndibenzylethylenediumine or N- 1 A compmmd according to Him 4 whcrcin Q i ethylpiperidine or an alkyl group of from one to seven H Carbon lIlOmS- 11. A compound according to claim 2 wherein n is ()i 2. A compound according to cluim I wherein X is 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 wherein X is
 3. A compound according to claim 1 wherein X is
 4. A compound according to claim 1 wherein X is
 5. A compound according to claim 2 wherein Q is -CH2OCOCH3.
 6. A compound according to claim 2 wherein Q is -CH3.
 7. A compound according to claim 3 wherein Q is -CH2OCOCH3.
 8. A compound according to claim 3 wherein Q is -CH3.
 9. A compound according to claim 4 wherein Q is -CH2OCOCH3.
 10. A compound according to claim 4 wherein Q is -CH3.
 11. A compound according to claim 2 wherein n is
 0. 